Therapeutic effect of intratracheal administration of murine IL-4 receptor antagonist on asthmatic airway inflammation.
OBJECTIVE
It is well known that IL-4 and IL-13 play critical roles in the pathogenesis of asthma. In this study, by overexpressing murine IL-4 receptor antagonist (mIL-4RA), a competitive antagonist for both IL-4 and IL-13, we investigated the therapeutic effects of mIL-4RA on mouse asthmatic airway inflammation.


METHODS
BALB/c mice were randomly divided into four groups: healthy control mice; ovalbumin (OVA) sensitized/challenged mice; OVA sensitized/challenged mice intratracheally administered with mIL-4RA plasmid (mIL-4RA group); and OVA sensitized/challenged mice intratracheally administered with control plasmid (control plasmid group). The airway inflammation was determined by histopathological examinations. Cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to analyze CD4 and CD8 T-lymphocyte subsets.


RESULTS
Compared to the control plasmid-treated mice, intratracheal administration of mIL-4RA expressing plasmid on the sensitization phase protected the mice from the subsequent induction of asthmatic airway inflammation. The eosinophilic infiltration in bronchoalveolar lavage fluid (BALF) was significantly reduced compared to that of the control (p < 0.01). Interestingly, intratracheal administration of mIL-4RA regulated the Th1/Th2 cytokine imbalance in local airway with increased IL-13 levels and decreased IFN-gamma levels compared to the control plasmid group. However, although we did see the decreased level of IL-4 and IL-13 in serum, the serum level of IFN-gamma is not changed in the mIL-4RA group, suggesting that mIL-4RA could not correct the imbalance of Th1/Th2 cytokines in serum. In addition, intratracheal administration of mIL-4RA had no effect on the ratio of CD4/CD8 T-lymphocyte subsets in the peripheral blood, lung, or spleen.


CONCLUSIONS
This study demonstrated that intratracheal administration of mIL-4RA attenuated the asthmatic inflammation and regulated the Th1/Th2 cytokine imbalance in local airway with minimal systemic effects. This method may serve as a potential therapeutic option for treating asthma.
Tian
Daiyin
D
Department of Respiratory Medicine, Children's Hospital, Chongqing Medical University, ChongQing, PR China.
Fu
Zhou
Z
Liu
Enmei
E
He
Yunfeng
Y
Wang
Xiaofang
X
Wang
Lijia
L
D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D001992:Bronchoalveolar Lavage Fluid; D002460:Cell Line; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000494:pharmacology; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014162:Transfection; D053662:Interleukin-4 Receptor alpha Subunit
D018076:DNA, Complementary; D007371:Interferon-gamma; D018793:Interleukin-13; D015847:Interleukin-4; D010047:Ovalbumin; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit